Note: Within nine months of the publication of the mention of the grant of the European patent in the European PatentBulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with theImplementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has beenpaid. (Art. 99(1) European Patent Convention).

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(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention of the grant of the patent: 04.07.2012 Bulletin 2012/27

(21) Application number: 10167756.5

(22) Date of filing: 17.03.2003

(51) Int Cl.:A61B 18/02 (2006.01) A61F 7/10 (2006.01)

(54) Devices for selective disruption of fatty tissue by controlled cooling

Vorrichtungen zur selektiven Spaltung von Fettgewebe durch gesteuerte Kühlung

Dispositifs pour la dislocation sélective d’un tissu gras par refroidissement contrôlé

(84) Designated Contracting States: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

(30) Priority: 15.03.2002 US 365662 P

(43) Date of publication of application: 20.10.2010 Bulletin 2010/42

(62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 07117532.7 / 1 917 93503716609.7 / 1 490 005

(73) Proprietor: The General Hospital CorporationBoston, MA 02114 (US)

(72) Inventors: • Anderson, Richard, Rox

Boston, MA 02114-3130 (US)• Manstein, Dieter

Boston, MA 02114-3130 (US)

(74) Representative: Maiwald Patentanwalts GmbHElisenhof Elisenstrasse 380335 München (DE)

(56) References cited: GB-A- 2 286 660 US-A- 4 869 250US-A- 5 339 541 US-A- 6 017 337US-A1- 2001 023 364

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Description

FIELD OF THE INVENTION

[0001] The present invention relates to devices for use in the selective disruption of lipid-rich cells by controlled cooling.The present invention further relates to a device for use in carrying out the methods for selective disruption of lipid-richcells by controlled cooling. Other aspects of the invention are described in or are obvious from the following disclosure(and within the ambit of the invention).

BACKGROUND

[0002] The subcutaneous fatty tissue of newborns is unusually sensitive to the cold. In newborns, the intracellular lipidcontent of the subcutaneous fat cells, or "adipocytes," comprises increased ratios of highly saturated triglycerides. Evenmoderately cold temperatures can adversely affect cells having a highly saturated lipid content, rendering newbornsubcutaneous fatty tissue vulnerable to adipocyte necrosis following exposure to the cold. Hypothermia of subcutaneousfatty tissue can result in associated inflammation of the dermis and/or epidermis. For example, disorders of cold pan-niculitis in newborns are known to produce painful skin lesions.[0003] As newborns mature, the ratio of saturated to unsaturated fatty acids among intracellular triglycerides of adi-pocytes gradually decreases. Having a higher content of unsaturated fatty acids is more protective against the cold, andthe occurrence of cold panniculitis in infants gradually subsides. For detailed reviews on the subject of cold panniculitis,see Epstein et al. (1970) New England J. of Med. 282(17):966-67; Duncan et al. (1966) Arch. Derm. 94:722-724; Kellumet al. (1968) Arch. Derm. 97:372-380; Moschella, Samuel L. and Hurley, Harry J. (1985) Diseases of the Corium andSubcutaneous Tissue. In Dermatology (W.B. Saunders Company):1169 -1181; John C Maize (1998) Panniculitis InCutaneous Pathology (Churchill Livingstone): 327-344; Bondei, Edward E. and Lazarus, Gerald S. (1993) Disorders ofSubcutaneous Fat (Cold Panniculitis). In Dermatology in General Medicine (McGraw-Hill, Inc.): 1333-1334[0004] In adults, the intracellular lipid content varies among cell types. Dermal and epidermal cells, for instance, arerelatively low in unsaturated fatty acids compared to the underlying adipocytes that form the subcutaneous fatty tissue.For a detailed review of the composition of fatty tissue in mammals, see Renold, Albert E. and Cahill, Jr., George F.(1965) Adipose Tissue. In Handbook of Physiology (American Physiology Society):170-176. As a result, the differentcell types, e.g., lipid-rich and non-lipid-rich cells, have varying degrees of susceptibility to the cold. In general, non-lipid-rich cells can withstand colder temperatures than lipid-rich cells.[0005] It would be highly desirable to selectively and non-invasively damage adipocytes of the subcutaneous fattytissue without causing injury to the surrounding dermal and epidermal tissue. Both health and cosmetic benefits areknown to result from reduction of fatty tissue, however, current methods, such as liposuction, involve invasive procedureswith potentially life threatening risks (e.g., excessive bleeding, pain, septic shock, infection and swelling).[0006] Current methods for non-invasive removal of subcutaneous fatty tissue include the use of radiant energy andcooling solutions. U.S. Patent No.s 5,143,063, 5,507,790 and 5,769,879 describe methods for using radiant energy toreduce subcutaneous fatty tissue, however, the applied energy levels are difficult to control and often there is collateraldamage to the dermis and/or epidermis. Cooling solutions proposed by WO 00/44346 do not stabilize skin surfacetemperatures and therefore, also fail to adequately protect against collateral damage to the dermis and/or epidermis.[0007] A previous study conducted in Guinea Pigs described the removal of subcutaneous fatty tissue by cryo-damage.Burge, S. and Dawber, R. (1990) Cryobiology 27:153-163. However this result was achieved using relatively aggressivecooling modalities (e.g., liquid nitrogen), which induced epidermal damage. Ideally, removal of subcutaneous fatty tissueby cooling would not cause associated damage to the epidermis.[0008] Temperature controlled methods and devices for selectively damaging lipid-rich cells (e.g., adipocytes com-prising the subcutaneous fatty tissue) without causing injury to non lipid-rich cells (e.g., dermis and/or epidermis) wereheretofore unknown. GB 22 86 660 discloses a skin cooling device.

SUMMARY

[0009] The invention is defined in the independent claims. It has now been shown that adipose tissue comprising lipid-rich cells can be selectively disrupted without causing injury to the surrounding non lipid-rich tissue (e.g., dermal andepidermal tissue) by controlling the temperature and/or pressure applied to the respective tissues.[0010] Disclosed is a cooling method for selective disruption of lipid-rich cells in a non-infant human subject comprisingapplying a cooling element proximal to the subject’s skin to create a temperature gradient within a local region sufficientto selectively disrupt and thereby reduce the lipid-rich cells of said region, and, concurrently therewith maintain thesubject’s skin at a temperature wherein non lipid-rich cells proximate to the cooling element are not disrupted.[0011] Disclosed is also a method for treating a region of a subject’s body to achieve a desired reduction in subcutaneous

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adipose tissue, comprising a) applying a cooling element proximal to the subject’s skin in the region where subcutaneousadipose tissue reduction is desired to create a temperature gradient within said region sufficient to selectively disruptlipid-rich cells therein, and, simultaneously therewith maintain the subject’s skin at a temperature wherein non lipid-richcells proximate to the cooling element are not disrupted; b) repeating the application of the cooling element to thesubject’s skin of step (a) a plurality of times until the desired reduction in subcutaneous adipose tissue has been achieved.[0012] Described is a device for selectively disrupting lipid-rich cells in a non-infant human subject by cooling com-prising: means for creating a temperature gradient within a local region of the subject’s skin to selectively disrupt andthereby reduce lipid-rich cells of the region, while, concurrently therewith, maintaining the subject’s skin at a temperaturewhereby non lipid-rich cells are not disrupted.[0013] Described is an apparatus for locally reducing lipid-rich cells, comprising a treatment device operable to receivea cooling agent; a cooling agent source connected to the treatment device for supplying said cooling agent; a controlunit coupled to the treatment device and the cooling agent source for controlling a cooling temperature of said coolingagent, wherein said treatment device exposes target tissue to said cooling agent, which selectively induces damage tolipid-rich cells at said target tissue.[0014] Described is an apparatus for locally reducing lipid-rich cells, comprising a means for setting a cooling agentto a predetermined temperature; and a means for applying said cooling agent to target tissue, whereby the cooling agentselectively induces damage to lipid-rich cells at said target tissue.[0015] These and other objects and embodiments are described in or are obvious from and within the scope of theinvention, from the following Detailed Description.

DESCRIPTION OF THE DRAWINGS

[0016]

Figure 1A illustrates a treatment system.Figure 1B depicts a diagram illustrating a configuration of control unit.Figure 1C depicts a diagram showing cooling/heating element.Figure 1D illustrates a flat cooling treatment system with a probe controller.Figure 2A illustrates a treatment system for cooling lipid-rich cells within a skin fold.Figure 2B illustrates a treatment system for cooling lipid-rich cells within a skin fold with a probe controller.Figure 3A illustrates a treatment system that includes a suction unit.Figure 4 illustrates a treatment system that is combined with suction system to provide treatment of an isolated area.Figure 5A, B illustrate a treatment system which can enclose circumferentially a target tissue mass.Figure 6 depicts an image of the skin surface showing indentation after 17 days at some areas matching coldexposure sites.Figure 7 depicts histology of the subcutaneous adipose tissue 17 days after cold exposure (Pig II, Site E). Figure7A shows the low magnification view and Figure 7B shows the high magnification view.Figure 8A, B depicts Site C; 8 C, D depicts Site E; and 8 E, F depicts Site F; each of which show histology of thesubcutaneous adipose tissue 17 days after cold exposure (Pig II, Site C, E and F).Figure 9 depicts an image of the device used to administer cooling to Pig III.Figure 10A, B, C, D, E, F, G, H, I, and J depicts temperature plots of the exposure sites 1, 2, 7, 11, 12, 13, 14, 15,16 and 18 of Pig III in various tissue depths.Figure 11 depicts an ultrasound image of test Site 11, 3.5 months after exposure.Figure 12A, B depicts histology of test Site 8, 6 days after exposure. Figure 12C, D depicts histology of test Site 9(control).Figure 13A, B, C, D, and E depicts macroscopic sections through the center of test Sites 1, 3, 11, 12 and 18, 3.5months after exposure.

DETAILED DESCRIPTION

[0017] The present disclosure relates to a method for locally reducing adipose tissue comprising applying a coolingelement to a subject at a temperature sufficient to selectively disrupt lipid-rich cells, wherein the temperature does notproduce unwanted effects in non lipid-rich cells. Preferably, the cooling element is coupled to or contains a cooling agent.[0018] Disclosed is a cooling method for selective disruption of lipid-rich cells in a non-infant human subject comprisingapplying a cooling element proximal to the subject’s skin to create a temperature gradient within a local region sufficientto selectively disrupt and thereby reduce the lipid-rich cells of said region, and, concurrently therewith maintain thesubject’s skin at a temperature wherein non lipid-rich cells proximate to the cooling element are not disrupted.[0019] Disclosed is also a method for treating a region of a subject’s body to achieve a desired reduction in subcutaneous

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adipose tissue, comprising a) applying a cooling element proximal to the subject’s skin in the region where subcutaneousadipose tissue reduction is desired to create a temperature gradient within said region sufficient to selectively disruptlipid-rich cells therein, and, simultaneously therewith maintain the subject’s skin at a temperature wherein non lipid-richcells proximate to the cooling element are not disrupted; b) repeating the application of the cooling element to thesubject’s skin of step (a) a plurality of times until the desired reduction in subcutaneous adipose tissue has been achieved.[0020] Cooling elements of the present invention can contain cooling agents in the form of a solid, liquid or gas. Solidcooling agents can comprise, for example thermal conductive materials, such as metals, metal plates, glasses, gels andice or ice slurries. Liquid cooling agents can comprise, for example, saline, glycerol, alcohol, or water/alcohol mixtures.Where the cooling element includes a circulating cooling agent, preferably the temperature of the cooling agent isconstant. Salts can be combined with liquid mixtures to obtain desired temperatures. Gasses can include, for example,cold air or liquid nitrogen.[0021] In one embodiment, cooling elements can be applied such that direct contact is made with a subject, via eitherthe agent or the element. In another embodiment, direct contact is made via the agent alone. In yet another embodiment,no direct contact is made via either the agent or the element; cooling is a carried out by proximal positioning of thecooling element and/or agent.[0022] Preferably, the temperature of the cooling agent is less than about 37°C, but not less than -196°C (i.e, thetemperature of liquid nitrogen).[0023] Preferably, the temperature range of the administered cooling element is between about 40°C and -15°C, evenmore preferably between 4°C and -10°C if the cooling agent is a liquid or a solid. Generally, the cooling element ispreferably maintained at an average temperature of between about -15°C and about 35°C, 30°C, 25°C, 20°C, 154°C,10°C, or 5°C; about -10°C and about 35°C, 30°C, 25°C, 20°C, 15°C, 10°C, or 5°C; about -15°C and about 20°C, 15°C,10°C, or 5°C.[0024] The cooling element and/or agent can be applied for up to two hours. Preferably, the cooling element is appliedfor between 1 to 30 minutes. The cooling element can be applied for at least one hundred milliseconds (e.g., shorterdurations are envisioned, for instance, with sprays). For example, liquid nitrogen can be applied in very short intervals(e.g., about 1 second), repeatedly (e.g., about 10-100 times) and between applications, a temperature that does notcause epidermal damage is maintained (e.g., about 0°C to -10°C, depending on the length of exposure). In a gentlecooling regime, for example, the liquid nitrogen can be sprayed from a distance (e.g., from about 10 to 30 cm) whereinsome portion of the liquid nitrogen droplets evaporate during the spraying and/or mix with ambient air.[0025] Cooling elements and/or agents of the present invention are applied, for example, to the skin surface througheither direct or indirect contact. A subject’s skin comprises the epidermis, dermis or a combination thereof. The coolingelement and/or agent is a non-toxic cooling agent when applied directly to the skin surface.[0026] The cooling element and/or agent can be applied more than once, for example, in repetitious cycles. The coolingagent can be applied in a pulsed or continuous manner. The cooling element and/or agent can be applied by all con-ventional methods known in the art, including topical application by spray if in liquid form, gas or particulate solid material.Preferably, application is by external means, however, cooling elements and/or agents of the present invention can alsobe applied subcutaneously by injection or other conventional means. For example, the cooling agent can be applieddirectly to the subcutaneous tissue and then either removed after contact or left in the subcutaneous tissue to achievethermal equilibration and therefore cooling of the lipid-rich tissue (e.g., subcutaneous injection of a liquid cooling agentor of small cooling particles, such as pellets or microbeads).[0027] Preferably, methods of the present disclosure are non-invasive (e.g., superficial, laparoscopic or topical pro-cedures not requiring invasive surgical techniques).[0028] The cooling element and/or agent can be applied to one defined area or multiple areas. Spatial distribution ofthe cooling element and/or agent can be controlled as needed. Generally, the dimension of the surface area (e.g., wherethe cooling agent is in contact with the skin) should be at least three times the depth of subcutaneous fatty tissue thatis targeted for cooling. Preferably, the minimum diameter of the surface area is at least 1 cm2. Even more preferably,the diameter of the surface area is between 3 to 20 cm2. Determination of the optimal surface area will require routinevariation of several parameters. For example, larger surface areas, such as those over 3500 cm2, can be cooled accordingto the methods of the present invention if hypothermia is prevented by additional means. Hypothermia can be preventedby compensating for the heat transfer away from the body at other sites (e.g., applying warm water at one or moreadditional sites). Multiple cooling elements and/or agents can be employed, for example, in contacting larger surfaceareas (e.g., greater than 3500 cm2).[0029] The cooling element and/or agent can follow the contour of the area to which it is applied. For example, aflexible apparatus can be used to follow the contour of the surface area where cooling is applied. The apparatus canalso modify the shape of the contacted surface such that the surface is contoured around or within the cooling agent orthe apparatus containing the cooling agent upon contact. The cooling element and/or agent can contact more than onesurface at once, for example, when the surface is folded and contacted on either side by the cooling element and/oragent. Preferably, a skin fold is contacted on both sides by the cooling element and/or agent to increase the efficiency

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of cooling.[0030] Preferably, the solid cooling element and/or agent is shaped to enhance thermodynamic heat exchange ("ther-mal exchange") at the contacted surface (e.g., skin surface). In order to enhance conduction, a liquid can be used atthe interface between the solid cooling agent and the contacted surface.[0031] Where necessary, application of the cooling element and/or agent can be coupled with use of a pain managementagent, such as an anesthetic or analgesic (cooling alone has analgesic properties, thus use of additional pain managementagents is optional). Local anesthetics, for example, can be topically applied at the point of contact either before, after orduring application of the cooling agent. Where necessary, systemic administration of the anesthetic can be providedthrough conventional methods, such as injection or oral administration. The temperature of the cooling agent can bechanged during the treatment, for example, so that the cooling rate is decreased in order to provide a treatment causingless discomfort. In addition, methods of the present invention can be performed in combination with other fat reductionprocedures known in the art, such as liposuction.[0032] Preferably, lipid-rich cells of the present invention are adipocytes within subcutaneous fatty tissue or cellulite.Thus, lipid-rich cells comprising the subcutaneous adipose tissue are targeted for disruption by methods of the presentinvention. In addition, it is within the ambit of the invention to target disruption of lipid-rich cells comprising adventiciasurrounding organs or other internal anatomical structures.[0033] The intracellular lipids of adipocytes are confined within the paraplasmatic vacuole. There are univacular andplurivacular adipocytes within the subcutaneous fatty tissue. Most are univacular, and greater than about 100um indiameter. This size can increase dramatically in obese subjects due to an increase in intracellular lipid content.[0034] Preferably, lipid-rich cells of the present invention have a total intracellular lipid content of between 20-99 %.Preferably, lipid-rich cells of the present invention have an intracellular lipid content comprised of about 20- 50% saturatedtriglycerides, and even more preferably about 30-40% saturated triglycerides. Intracellular triglycerides include, but arenot limited to, saturated fatty acids e.g., myristic, palmitic and stearic acid; monounsaturated fatty acids, e.g., palmitoleicand oleic acid; and polyunsaturated fatty acids e.g., linoleic and linolenic acid.[0035] Preferably, lipid-rich cells of the present invention are located within subcutaneous adipose tissue. The saturatedfatty acid composition of subcutaneous adipose tissue varies at different anatomical positions in the human body. Forexample, human subcutaneous adipose tissue in the abdomen can have the following composition of saturated fattyacids: myristic (2.6 %), palmitic (23.8 %), palmitoleic (4.9%), stearic (6.5%), oleic (45.6%), linoleic (15.4 %) and linolenicacid (0.6%). The subcutaneous adipose tissue of the abdominal area can comprise about 35% saturated fatty acids.This is comparatively higher than the buttock area, which can comprise about 32% saturated fatty acids. At roomtemperature, saturated fatty acids of the abdominal area are in a semisolid state as a result of the higher fatty acidcontent. The buttock area is not similarly affected. Malcom G. et al., (1989) Am. J. Clin. Nutr. 50(2):288-91. One skilledin the art can modify temperature ranges or application times as necessary to account for anatomical differences in theresponse to cooling methods of the present invention.[0036] Preferably, non lipid-rich cells of the present invention have a total intracellular lipid content of less than 20%,and/or are not disrupted by cooling methods of the present invention. Preferably, non lipid-rich cells of the presentinvention include cells having an intracellular lipid content comprising less than about 20% highly saturated triglycerides,even more preferably less than about 7-10% highly saturated triglycerides. Non lipid-rich cells include, but are not limitedto, those surrounding the subcutaneous fatty tissue, such as cells of the vasculature, peripheral nervous system, epidermis(e.g., melanocytes) and dermis (e.g., fibrocytes).[0037] Damage to the dermis and/or epidermis that is avoided by the methods of the present invention can involve,for example, inflammation, imitation, swelling, formation of lesions and hyper or hypopigmentation of melanocytes.[0038] Without being bound by theory, it is believed that selective disruption of lipid-rich cells results from localizedcrystalization of highly saturated fatty acids upon cooling at temperatures that do not induce crystalization of highlysaturated fatty acids in non lipid-rich cells. The crystals rupture the bilayer membrane of lipid-rich cells, causing necrosis.Thus, damage of non lipid-rich cells, such as dermal cells, is avoided at temperatures that induce crystal formation inlipid-rich cells. It is also believed that cooling induces lipolysis (e.g., metabolism) of lipid-rich cells, further enhancing thereduction in subcutaneous adipose tissue. Lipolysis may be enhanced by local cold exposure inducing stimulation ofthe symapthetic nervous system.[0039] In one embodiment, the temperature of the lipid-rich cells is not less than about - 10°C. Preferably, the tem-perature of the lipid-rich cells is between -10°C and 37°C. More preferably, the temperature of the lipid-rich cells isbetween -4°C and 20°C. Even more preferably, the temperature of the lipid-rich cells is between -2°C and 15°C. Preferably,the lipid-rich cells are cooled to less than 37°C, for up to two hours. Generally, the lipid-rich cells are preferably maintainedat an average temperature of between about -10°C and about 37°C, 35, 30°C, 25°C, 20°C, 15°C, 10°C, or 4°C; about-4°C and about 35°C, 34°C, 25°C, 20°C, 15°C, 10°C, or 4°C; about -2°C and about 35, 30°C, 25°C, 20°C, 15°C, 10°C,or 5°C.[0040] In yet another embodiment, the temperature range of the lipid-rich cells oscillates between 37°C and -10°C.Methods of pulse cooling followed by brief periods of warming can be used to minimize collateral damage to non lipid-

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rich cells. More preferably, the temperature range of the lipid-rich cells oscillates between -8°C and 33°C. Even morepreferably, the temperature range of the lipid-rich cells oscillates between -2°C and 15°C. The temporal profile of thecooling of the skin can be performed in one continuous cooling act or in multiple cooling cycles or actually a combinationof cooling with active heating cycles.[0041] Cooling methods of the present invention advantageously eliminate unwanted effects in the epidermis. In oneembodiment, the temperature of the epidermis is not less than about -15°C. Preferably, the temperature of the epidermisis between about - 10°C and 35°C. More preferably, the temperature of the epidermis is between about - 5°C and 10°C.Even more preferably, the temperature of the epidermis is between about -5°C and 5°C.[0042] Cooling methods of the present disclosure advantageously eliminate unwanted effects in the dermis. In oneembodiment, the temperature of the dermis is not less than about -15°C. Preferably, the temperature of the dermis isbetween about -10°C and 20°C. More preferably, the temperature of the dermis is between about -8°C and 15°C. Evenmore preferably, the temperature of the dermis is between about -5°C and 10°C. In a preferred embodiment, the lipid-rich cells are cooled to about -5°C to 5°C for up to two hours and the dermal and epidermal cells maintain an averagetemperature of about 0°C. In a most preferred embodiment, the lipid-rich cells are cooled to about -5 to 15°C for timesranging from about a minute, up to about two hours.[0043] Methods of the present disclosure can be applied in short intervals (e.g., 1 minute, 5 minute, 15 minute, 30minute and 60 minute time intervals) or long intervals (e.g., 12 hour and 24 hour time intervals). Preferably intervals arebetween 5 and 20 minutes. Heat can optionally be applied between intervals of cooling.[0044] Feedback mechanisms can be employed to monitor and control temperatures in the skin (i.e., dermis, epidermisor a combination thereof) subcutaneous adipose tissue. A feedback mechanism can monitor the temperature of asubject’s skin to ensure that the temperature therein in does not fall below a predetermined minimum temperature, forexample, about -10°C to about 30°C. A non-invasive device can be externally applied to measure surface temperatureat the point of contact and/or the surrounding region. An invasive device, such as a thermocouple, can be used tomeasure internal temperatures.[0045] Feedback mechanisms can include all known in the art to monitor temperature and/or crystal formation. Crystalformation can be measured, for example by ultrasound imaging and acoustical, optical, and mechanical measurements.Mechanical measurements can include, for example, measurements of tensile strength.[0046] In one embodiment, a multilayer model can be employed to estimate temperature profiles over time and withindifferent depths. Temperature profiles are designed to produce a temperature gradient within the tissue, having a lowertemperature at the surface. In a preferred embodiment, temperature profiles are designed to minimize blood flow duringcooling. Feedback mechanisms comprising, for example, thermocouples, ultrasound (e.g., to detect phase changes ofthe subcutaneous adipose tissue) or shock wave propagation (e.g., propagation of a shock wave is altered if a phasetransition occurs) can be employed to achieve optimal temperature gradients.[0047] Substantial cooling of the subcutaneous adipose layer, for example to a target temperature between about-5°C and 15°C, by cooling at the skin surface has several requirements. Heat extracted from the skin surface establishesa temperature gradient within the skin, which in turn cools first the epidermis, dermis, and finally subcutaneous adiposelayers. Dermal blood flow brings heat from the body core to the dermis. Dermal blood flow can therefore severely limitcooling of the deep dermis and subcutaneous adipose. Therefore, it is strongly preferred to temporarily limit or eliminatecutaneous blood flow, for example by locally applying a pressure to the skin greater than the systolic blood pressure,while cooling as a treatment to achieve reduction in subcutaneous adipose. A general requirement is that the time ofcooling at the skin surface must be long enough to allow heat to flow from the dermis and subcutaneous adipose layersin order to achieve the desired temperature for treatment of the same. When the subcutaneous adipose is cooled to atemperature below that for crystallization of its lipids, the latent heat of freezing for these lipids must also be removed,by diffusion. The skin surface cooling temperature and cooling time can be adjusted to control depth of treatment, forexample the anatomical depth to which subcutaneous adipose is affected. Heat diffusion is a passive process, and thebody core temperature is nearly always close to 37°C. Therefore, another general requirement is that the skin surfacetemperature during cooling, must be lower than the desired target (e.g., adipocytes) temperature for treatment of theregion, for at least part of the time during which cooling is performed.[0048] When cooling a diameter of skin greater than about 2 cm, and with no blood flow, one-dimensional heat diffusionoffers a good approximation for estimating temperature profiles in skin over time during cooling. Heat diffusion is governedby the general diffusion equation, δT/δt = κ δ2T/δz2, where T (z,t) is the temperature in skin as a function of depth z andtime t, and κ is the thermal diffusivity, which is approximately 1.3 x 10-3 cm2s-1 for skin tissue. Solutions and approximatesolutions to the heat diffusion equation have been made for planar geometry of a semi-infinite slab, approximating thesituation for skin. When the surface of the skin (z = 0) is held at a given lower temperature, a useful approximation isthat heat flow from a depth z requires a time of approximately t ≅ z2 to achieve a temperature difference � of the initialdifference, where t is in seconds and z is in millimeters. Thus, z2 can be considered an approximate value for a thermaltime constant. For example, if the initial skin temperature is 30 C, and ice at 0 C is placed firmly against the skin surface,it requires about 1 second for the temperature at a depth of I millimeter, to reach about 15 C. The subcutaneous fat layer

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typically begins at about z ≅ 3 mm, and extends for millimeters up to many centimeters thick. The thermal time constantfor heat transfer from the top of the subcutaneous adipose layer, is therefore about 10 seconds. To achieve substantialcooling of subcutaneous adipose, at least several and preferably greater than 10 thermal time constants of cooling timeare required. Therefore, cooling must be maintained for about 30-100 seconds at the skin surface, and in the absenceof dermal blood flow, for the temperature of the topmost portion of subcutaneous adipose to approach that of the cooledskin surface. The latent heat of crystallization for lipids, mentioned above, must also be removed when the fat temperaturedrops below that for crystallization. Therefore in general, cooling times over 1 minute are desired, and cooling timesgreater than about 1 minute can be used to adjust the depth of adipocytes affected, for times up to more than an hour.[0049] Accordingly, in yet another embodiment, the dermis is cooled at a rate sufficient to induce vasoconstriction.Blood circulation within the dermis stabilizes the temperature of the dermis close to body temperature. In order to coolsubcutaneous adipose tissue to temperatures below body temperature, blood flow can be minimized. Fast cooling ofthe epidermal surface can achieve reflectory vasoconstriction that limits blood circulation in an appropriate way.[0050] In yet another embodiment, a vasoconstrictive drug is administered to induce vasoconstriction. Vasoconstrictivedrugs, for example, can be topically applied at the point of contact either before, after or during application of the coolingagent. Where necessary, systemic administration of the vasoconstrictive drug can be provided through conventionalmethods, such as injection or oral administration. The vasoconstrictive drug can be any known in the art. Preferably,the vasoconstrictive drug is EMLA cream or epinephrine.[0051] In yet another embodiment, pressure is applied to a surface, either at the point of contact with the cooling agentor in proximity thereto, such that lateral blood flow is limited. Pressure can be applied, for example, to a skin surface bycompressing the skin surface into a skin fold comprising single or multiple folds. Pressure can also be by applying avaccum either at the point of contact with the cooling agent or in proximity thereto.[0052] Without being bound by theory, it is believed that the rate of formation of crystals in lipid-rich cells can be alteredby the application of pressure during the cooling process. Sudden crystalization, rather than a slow accumulation ofcrystals, would cause greater damage to the lipid-rich cells. It is also believed that the application of pressure can forcethe movement of the crystals within the lipid-rich cells, enhancing the damage to the bilayer membrane. Furthermore,different compartments of the subcutaneous adipose tissue have different viscosities. In general, the viscositiy is en-hanced at colder temperatures (e.g., those particulary close to the point of phase change). Because the phase changefor lipid-rich cells occurs at higher temperatures than non lipid-rich cells, non-uniform tension lines form within thesubcutaneous adipose tissue upon the application of pressure. It is believed that pronounced damage occurs withinthese tension lines.[0053] In yet another aspect, the temperature of the dermis and/or epidermis oscillates between 35°C and -15°C.More preferably, the temperature of the dermis and/or epidermis oscillates between -10°C and 10°C. Even more pref-erably, the temperature of the dermis and/or epidermis oscillates between -8°C and 8°C. Oscillating temperatures atthe skin surface can provide intermittent warming to counteract potential side effects of the cooling process (e.g., crystalformation in the dermal or epidermal cells).[0054] In yet another aspect, application of the cooling agent is coupled with the application of electric or acousticfields, either constant or oscillating in time, localized in the dermis and/or epidermis to reduce or eliminate crystal formationtherein.[0055] Figure 1A illustrates a treatment system 100 for cooling a target area As shown in Figure 1A, treatment system100 may include a control unit 105 and a treatment unit 107, which may include a cooling/heating element 110 and atreatment interface 115.[0056] Control unit 105 may include a power supply, for example, control unit may be coupled to a power source, forsupplying power to treatment unit 107. Control unit 105 can also include a computing device having control hardwareand/or software for controlling, based on inputted properties and/or parameters, cooling/heating element 110 and treat-ment interface 115. Treatment interface 115 can include a detector 120.[0057] Figure 1B is a diagram illustrating a configuration of control unit 105 in accordance with an embodiment of theinvention. As shown in Figure 1B, control unit 105 can comprise a computing device 125, which can be a general purposecomputer (such as a PC), workstation, mainframe computer system, and so forth. Computing device 125 can include aprocessor device (or central processing unit "CPU") 130, a memory device 135, a storage device 140, a user interface145, a system bus 150, and a communication interface 155. CPU 130 can be any type of processing device for carryingout instructions, processing data, and so forth. Memory device 135 can be any type of memory device including anyone or more of random access memory ("RAM"), read-only memory ("ROM"), Flash memory, Electrically ErasableProgrammable Read Only Memory ("EEPROM"), and so forth. Storage device 140 can be any data storage device forreading/writing from/to any removable and/or integrated optical, magnetic, and/or optical-magneto storage medium, andthe like (e.g., a hard disk, a compact discread-only memory "CD-ROM", CD-ReWritable "CD-RW", Digital Versatile Disc-ROM "DVD-ROM", DVD-RW, and so forth). Storage device 140 can also include a controller/interface (not shown) forconnecting to system bus 150. Thus, memory device 135 and storage device 140 are suitable for storing data as wellas instructions for programmed processes for execution on CPU 130. User interface 145 may include a touch screen,

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control panel, keyboard, keypad, display or any other type of interface, which can be connected to system bus 150through a corresponding input/output device interface/adapter (not shown). Communication interface 155 may be adaptedto communicate with any type of external device, including treatment unit 107. Communication interface 155 may furtherbe adapted to communicate with any system or network (not shown), such as one or more computing devices on a localarea network ("LAN"), wide area network ("WAN"), the internet, and so forth. Interface 155 may be connected directlyto system bus 150, or can be connected through a suitable interface (not shown). Control unit 105 can, thus, providefor executing processes, by itself and/or in cooperation with one or more additional devices, that may include algorithmsfor controlling treatment unit 107 in accordance with the present invention. Control unit 105 may be programmed orinstructed to perform these processes according to any communication protocol, programming language on any platform.Thus, the processes may be embodied in data as well as instructions stored in memory device 135 and/or storage device140 or received at interface 155 and/or user interface 145 for execution on CPU 130.[0058] Referring back to Figure 1A, treatment unit 107 may be a handheld device, an automated apparatus, and thelike. Cooling/heating element 110 can include any type of Cooling/heating component, such as a thermoelectric coolerand the like.[0059] Figure 1C is a diagram showing cooling/heating element 110 As shown in Figure 1C, cooling/heating element110 can include a network of passages where a cooling/heating fluid flows through. The passages may be formed byany heat conducting tubing and the like. The cooling/heating fluid can be directed into element 110 through an input 175and expelled through an output 180. The cooling/heating fluid may be any fluid having a controlled temperature, suchas cooled air/gas or liquid. For example, a saltwater or acetone bath that is cooled using ice or frozen carbon dioxidemay be used as a source of cooled liquid pumped through element 110. A circulating system may, thus, be formedwhere fluid expelled at output 180 is re-cooled at the fluid source and redirected into input 175. The temperature of thefluid source and/or element 110, which may include the rate at which cooling fluid is pumped through element 110, canbe monitored and controlled by control unit 105. Thus, the temperature of cooling/heating element 110 can be controlledor programmed using control unit 105. As further shown in Figure 1C, there can be a temperature difference, ∆T, betweenregions of element 110. For example, heat from the target tissue may be transferred to the cooling fluid during treatmentcausing fluid near output 180 to have a higher temperature than the cooling fluid near input 175. Such ∆T may be reducedby reducing the size of element 110. In accordance with an embodiment of the invention, the configuration of the passagesin element 110 and the corresponding application of element 110 to target tissue can account for any difference intemperature needed for treating various tissue targets. For example, the region of element 110 near exit 180 can beapplied to treatment areas requiring a higher treatment temperature, and so forth. The passages of element 110 can,thus, be configured in accordance with the size, shape, formation, and so forth, of target tissue that require the varioustreatment temperatures. Cooling/heating fluid can also be pumped through element 110 in a pulsing manner. Referringback to Figure 1A, treatment interface 115 can be any type of interface between cooling/heating element 110 and theepidermis 160 for effecting treatment onto the epidermis 160, dermis 165 and fat cells 170. For example, treatmentinterface 115 may include a cooling (conductive) plate, a cooling fluid-filled vessel, a free-forming membrane (for acomplementary interface with an uneven epidermis), a convex cooling element (for example, as shown in Figure 3), andthe like. Preferably, treatment interface 115 comprises a heat conducting material that complements the epidermis 160for maximum heat transfer between cooling/heating element 110 and the epidermis 160, dermis 165 and/or fat cells170. For example, treatment interface 115 can be a fluid-filled vessel or a membrane so that the change in pressurefrom cooling element 110 caused by a pulsing flow of cooling fluid may be transferred to the target tissue. Furthermore,treatment interface 115 may simply be a chamber where cooling/heating fluid may be applied directly to the target tissue(epidermis 160, dermis and fat cells 170), for example by using a spraying device and the like.[0060] Detector 120 can be a temperature monitor, for example, a thermocouple, a thermistor, and the like. Detector120 may include any thermocouple type, including Types T, E, J, K, G, C, D, R, S, B, for monitoring tissue cooling.Detector 120 may also include a thermistor, which can comprise thermally-sensitive resistors whose resistances changewith a change in temperature. The use of thermistors may be particularly advantageous because of their sensitivity. Inaccordance with an embodiment of the invention, a thermistor with a large negative temperature coefficient of resistance("NTC") can be used. Preferably, a thermistor used for detector 120 may have a working temperature range inclusiveof about -15°C to 40°C. Furthermore, detector 120 can include a thermistor with active elements of polymers or ceramics.A ceramic thermistor may be most preferable as these can have the most reproducible temperature measurements. Athermistor used for detector 120 can be encapsulated in a protective material such as glass. Of course, various othertemperature-monitoring devices can also be used as dictated by the size, geometry, and temperature resolution desired.Detector 120 can also comprise an electrode which can be used to measure the electrical resistance of the skin surfacearea. Ice formation within superficial skin structures like the epidermis or dermis causes an increased electrical resistance.This effect can be used to monitor ice formation within the dermis. Detector 120 can further consist of a combination ofseveral measurement methods.[0061] Detector 120 can, thus, extract, inter alia, temperature information from the epidermis 160, dermis 165 and/orfat cells 170 as feedback to control unit 105. The detected temperature information can be analyzed by control unit 105

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based on inputted properties and/or parameters. For example, the temperature of fat cells 170 may be determined bycalculation based on the temperature of the epidermis 160 detected by detector 120. Thus, treatment system 100 maynon-invasively measure the temperature of fat cells 170. This information may then be used by control unit 105 forcontinuous feedback control of treatment unit 107, for example, by adjusting the energy/temperature of cooling/heatingelement 110 and treatment interface 115, thus maintaining optimal treatment temperature of target fat cells 170 whileleaving surrounding epidermis 160 and dermis 165 intact. As described above, the cooling/heating element 110 canprovide adjustable temperatures in the range of about - 10°C up to 42°C. An automated temperature measurement andcontrol sequence can be repeated to maintain such temperature ranges until a procedure is complete.[0062] It is noted that adipose tissue reduction by cooling lipid-rich cells may be even more effective when tissuecooling is accompanied by physical manipulation, for example, massaging, of the target tissue. In accordance with anembodiment of the present invention, treatment unit 107 can include a tissue massaging device, such as a vibratingdevice and the like. Alternative a piezoelectric transducer can be used within treatment unit 107 I order to providemechanical oscillation or movement of the cooling /heating element 107 (or better treatment unit?). Detector 120 caninclude feedback devices for detecting changes in skin viscosity to monitor the effectiveness of treatment and/or toprevent any damage to surrounding tissue. For example, a vibration detecting device can be used to detect any changein the resonant frequency of the target tissue (or surrounding tissue), which can indicate a change in tissue viscosity,being mechanically moved or vibrated by a vibrating device contained in treatment unit 107.[0063] To further ensure that the epidermis 160 and/or the dermis 165 is not damaged by cooling treatment, an opticaldetector/feedback device can be used to monitor the change of optical properties of the epidermis (enhanced scatteringif ice formations occur); an electrical feedback device can be used to monitor the change of electric impedance of theepidermis caused by ice formation in the epidermis; and/or an ultrasound feedback device may be used for monitoringice formation (actually to avoid) in the skin. Any such device may include signaling control unit 105 to stop or adjusttreatment to prevent skin damage.[0064] In accordance with an embodiment of the invention, treatment system 100 may include a number of configu-rations and instruments. Algorithms that are designed for different types of procedures, configurations and/or instrumentsmay be included for control unit 105.[0065] As shown in Figure 1D, treatment system 100 may include a probe controller 175 and a probe 180 for minimalinvasive temperature measurement of fat cells 170. Advantageously, probe 180 may be capable of measuring a moreaccurate temperature of fat cells 170, thereby improving the control of treatment unit 107 and the effectiveness oftreatment.[0066] It is noted that treatment system 100 may be controlled remotely. For example, the link between control unit105 and treatment unit 107 may be a remote link (wired or wireless) providing control unit 105 remote control overcooling/heating element 110, treatment interface 115, probe controller 175, and probe 180.[0067] While the above exemplary treatment system 100 is illustrative of the basic components of a system suitablefor use with the present invention, the architecture shown should not be considered limiting since many variations of thehardware configuration are possible without departing from the present invention.[0068] Figure 2A illustrates a treatment system 200 for cooling fat cells 170 by folding the target tissue in accordancewith an embodiment of the invention. As shown in Figure 2A, treatment system 200 may include corresponding controlunits 105 and treatment units 107 on two sides coupled to a compression unit 205. Compression unit 205 may be adaptedto pull treatment units 107 together, thereby folding (or "pinching") target tissue (epidermis 160, dermis 165 and fat cells170) up between treatment units 107. The treatment interface 115 of the respective treatment units 107 on either sideof the target tissue may thus cool fat cells 170 from multiple sides with greater effectiveness, as described above.Detectors 120 can be included to measure and monitor the temperature of the target tissue. As shown in Figure 2A,control units 105 may be connected to form an integrated system. In accordance with an embodiment of the presentinvention, the various components of system 200 may be controlled using any number of control unit(s).[0069] As described before, physical manipulation of target tissue may improve the effectiveness of cooling treatment.In accordance with an embodiment of the present invention, compression unit 205 may vary the force with which treatmentunits 107 are pulled together around the target tissue (epidermis 160, dermis 165 and fat cells 170). For example,compression unit 205 can apply a pulsing force for alternately tightening and loosening the fold (or "pinch") of the targettissue. Resistance to the tightening can further be monitored for detecting any changes in the characteristics (for example,the viscosity) of the target tissue, and thus ensuring the effectiveness and safety of the treatment.[0070] Figure 2B illustrates system 200 with a probe 180 similar to that of system 100 shown in Figure 1C for minimalinvasive temperature measurement of fat cells 170. As described above, probe 180 may be capable of measuring amore accurate temperature of fat cells 170, thereby improving the control of treatment unit 107 and the effectiveness oftreatment.[0071] Figures 3A and 3B are diagrams showing a treatment system 300 in accordance with an embodiment of thepresent invention. As shown in Figure 3A, system 300 may include a suction unit 305, and treatment unit 107 may includetreatment interface 115 having a curved surface, which for example forms a dome, for forming and containing a chamber

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310 above the epidermis 160. As shown in Figure 3B, suction unit 305 may be activated to draw the air from chamber310 such that target tissue (epidermis 160, dermis 165 and fat cells 170) is pulled up into contact with treatment interface115. Advantageously, treatment interface 115 may surround target fat cells 170 for more effective cooling. Treatmentinterface 115 can consist of a solid stiff or flexible material, which is in contact with the skin or a thermal coupling agentbetween the skin surface and the treatment unit. The surface of the interface 115 can also have multiple openingsconnected to suction unit 305. The skin is partially entered into these muliple openings, which can increase the totalsurface area of the epidermis 160 in thermal contact to the treatment interface (e.g., stretching of the skin). Stretchingof the skin decreases the thickness of the epidermis and dermis, facilitating cooling of the fat 170. A number of detector(s) 120 and/or probe(s) 180 can be included in treatment system 300 for monitoring tissue temperature during treatment,as described above with reference to Figures 1A, 1C, 2A and 2B, detailed description of which will not be repeated here.[0072] Figure 4 illustrates a treatment system 400 in accordance with an embodiment of the invention. As shown inFigure 4, suction unit 305 can be connected to a ring opening around treatment interface 115 so that, when activated,a suction seal 410 is formed with the epidermis 160 around treatment interface 115. As a result, treatment can be effectedat treatment interface 115 to an isolated target tissue area.Advantageously, the subject or body part may be immersed in a warming bath and the treatment at interface 115 canbe unaffected. Consequently, treatment area can be increased while a surrounding warming environment can preventgeneral hypothermia.[0073] Figures 5A and 5B are diagrams showing a treatment system 500 in accordance with an embodiment of thepresent invention. As shown in Figures 5A and 5B, treatment system 500 may form a band (or cylinder) around a targettissue mass 515. Treatment system 500 may comprise any flexible or rigid material. Cooling/heating fluid can be pumpedthrough treatment system 500 via input 175 and output 180, as shown in Figure 5B. Cooling/heating element 110 canbe formed by an internal vessel or a network of passages, such as tubing and the like. Heat transfer with target tissuemass 515 can be effected via treatment interface 115, which can include any heat conducting material. Treatment system500 can further include a fastening mechanism 510, such as a hook and loop fastener and the like, for fastening andwrapping around tissue mass 515. Furthermore, treatment interface 115 can include a flexible material such that thepressure of cooling fluid pumped through treatment system 500 can be transferred to the target tissue 515. For example,with reference to Figure 5A, treatment system 500 can apply inward pressure to target tissue mass 515. Target tissuemass 515 can be any section, body part or extremity of a subject. For example, target tissue mass 515 can be an arm,the upper or lower leg, the waist, and so forth, of a subject. The pressure and flow of the cooling fluid in system 500 canbe controlled by control unit 105 to an optimal treatment temperature and/or pressure. A tight fit around tissue mass 515and increased inward pressure can also allow for the subject to be immersed in a warming bath. As described before,fluid flow can be a pulsing flow.[0074] The present invention is additionally described by way of the following illustrative, non-limiting Examples, thatprovide a better understanding of the present invention and of its many advantages

EXAMPLES

Example 1

Selective Damage to Fatty Tissue by Controlled Cooling In Vivo

[0075] Methods of the present disclosure were carried out on a white, 6 months old, female, Hanford miniature pig("Pig I") and a black, 6 months old, female Yucatan Miniature Pig ("Pig II"). The pigs were anesthetized using Telazol/Xylazine (4.4 mg/kg im + 2.2 mg/kg im). Inhalant anesthetics (Halothane or Isoflurane (1.5-3.0%) with Oxygen (3.0 L/min)was delivered by mask and filtered with an F-Air canister only if the injectable anesthetics did not provide enough somaticanalgesia. Several test sites were be marked with micro tattoos by applying India Ink to the corners of each test sites.After mapping of the test sites cold exposures were performed using a cooling device as described in Figure 1A. Thearea of the treatment interface was a flat area of the size of 2 x 4 cm2 with a built-in temperature sensor. The interfacewas in thermal contact with a thermoelectric chiller, which was electronically regulated by a control unit such that thetemperature at the surface of the interface was kept constant to a pre-set temperature. During the cold exposure thecooling device was applied to the skin with minor to moderate pressure that did not cause significant mechanical com-pression of blood flow. The cooling element was applied to the skin without any manipulation of the surface profile.[0076] Various combinations of pre-set cooling interface temperatures and exposure times were tested. For somesites a thermo-conductive lotion was applied between the skin and the cooling interface. This thermoconductive lotionconsisted mainly of glycerol. Pig I was observed for 61 days until excision biopsies from all test sites were procured andthe pig was sacrified. From test Site C there was an additional punch biopsy procured at day 2.[0077] The biopsies were processed for routine light microscopy and stained with Hematoxylin & Eosin. The indicatedtemperature is that of the applied cooling element. Table 1 depicts the parameters of the cooling application and the

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results obtained at various sites in Pig I:

[0078] Pig II was observed for 50 days until excision biopsies from all test sites were procured and the pig wassacrificed. From test Site E an additional biopsy was procured at day 17. The biopsies were processed for routine lightmicroscopy and stained with Hematoxylin & Eosin as described above. The indicated temperature is that of the appliedcooling element. Table 2 depicts the parameters of the cooling application and the results obtained at various sites in Pig II:

Table 1

Site Temperature Time Lotion Results

A -6°C At 61 days:1 minute + No epidermal damage.

No dermal damage.No obvious indentation.No obvious histological alterations.

B -6 °C 1 minute - At 61 days:No epidermal damage.No dermal damage.No obvious indentation.No obvious histological alterations.

C -6 °C 5 minutes + At 61 days:No epidermal damage.No dermal damage.Indentation due to loss of subcutaneous adipose tissue (1 week to 61 days).Decreased average size of adipocytes at a depth of between about 3-6 mm.Obvious histological damage to the adipose tissue.At 2 days:Tissue inflammation and panniculitis.

D -3.5 °C 5 minutes + At 61 days:No epidermal damage.No dermal damage.No obvious indentation.Borderline histological damage to the adipose tissue.Decreased average size of adipocytes.

E Control Normal- no changes within the epidermis, dermis and subcutaneous adipose tissue.

Table 2

Site Temperature Time Lotion Results

-6 °C 5 minutes At 50 days:C - Pronounced indentation (2-3 mm) due to loss of subcutaneous adipose

tissue.No epidermal damage.No dermal damage.No pigmentary changes, however, decreased size of adipocytes and histological damage to adipose tissue.

D -8 °C 5 minutes - At 50 days:Pronounced indentation (2-3 mm) due to loss of subcutaneous adipose tissue.

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[0079] Figure 6 depicts an image of the skin surface of test Sites D, E and F of Pig II, 17 days after exposure. Anindentation that matches the site of the cold exposure can be seen at 1, which mathches test Site D and 2, which matchestest Site E. No abnormal epidermal changes can be seen at these test sites. At 3, which matches the test Site F, whereaggressive cooling methods were applied, damage to the epidermis is pronounced (e.g., loss of pigmentation and acentral crust formation).[0080] Figure 7 depicts histology of test Site E (Pig II), 17 days after cold exposure at - 9°C for 5 minutes, in samplestaken from an area below the site of cold exposure. Figure 7A depicts a low power magnification (1,25x) and Figure 7Bdepicts a close up with medium power maginification (5x) of the same specimen. The epidermis 701, dermis 702,subcutaneous adipose 703 and muscle layer 704 are shown. The histology reveals signs of lobular and septal panniculitswithin subcutaneous adipose 703, which is an inflammation of the adipose tissue. The average size of fat cells isdecreased compared to the sample from the unexposed area. No evidence of tissue alterations is seen in the epidermis,dermis or muscle layer.[0081] A decrease in subcutaneous adipose tissue was demonstrated by clinical observation of indentation within theskin surface at the precise site of cooling, as well as by histology (Hematoxylin & Eosin staining). Figure 8A, B, C, D, E,and F depicts histology 50 days after exposure with low power maginification of 2.5x (Figures 8A, 8C and 8E) andmedium power maginification of 5x (Figures 8B, 8D and 8F) of test Site C (Figures 8A and 8B), test Site E (Figures 8Cand 8D) and test Site F (Figures 8E and 8F). The epidermis 801 and dermis 802 is not damaged in test Sites C and Ewhile the more aggressive cooling regime applied to test Site F resulted in damage to the epidermis and dermis (e.g.,scar formation and inflammation can be seen). The subcutaneous adipose 803 shows a decrease of adipocyte size andstructural changes (e.g., apparent condensation of the fat cell layer with fibrous septae is included in the condensatedfat layer). As a result of the aggressive cooling regime applied to test Site F, almost the entire layer was removed, leavingonly some residual fat cell clusters. Thus, where an aggressive cooling regime is applied (test Site F) non- selective andpronounced damage is observed in the epidermis and dermis.[0082] Taken together, the results demonstrate that selective disruption of subcutaneous adipose tissue is achievedusing cooling methods of the present invention without causing damage to the epidermis and dermis.[0083] Measurement of temperature during skin surface cooling at -7°C applied with pressure sufficient to stop skinblood flow, was performed to illustrate the time- and depth- dependence of cooling, in a live pig. Thermocouples insertedat depths of 0, 2, 4, and 8 millimeters were used to record temperature. Although the conditions of this experiment werenot ideal (the skin cooler did not maintain strictly 7°C at the surface), it is clear that cooling of the dermis (2 mm) and fat(4 mm, 8 mm) occurred generally as expected (see for example, Figure 10).

(continued)

Site Temperature Time Lotion Results

No epidermal damage.No dermal damage.No pigmentary changes, however, there was damage to the adipocytes to a depth of about 6 mm.Decreased size of adipocytes and histological damage to adipose tissue.

E -9 °C 5 minutes - At 50 days:Pronounced indentation (2-3 mm) due to loss of subcutaneous adipose tissue.No epidermal damage.No dermal damage.No pigmentary changes, however, there was damage to the adipose cells to a depth of about 6 mnn.Decreased size of adipocytes and histological damage to adipose tissue.At 17 days:Signs of panniculitis.

F -22 °C 5 minutes - At 50 days:Pronounced epidermal damage with pronounced hypopigmentation.Scar formation with dermal contraction and complete ablation of the subcutaneous adipose tissue.

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Example 2

Temperature profile Measurement at Various Tissue Depths

[0084] This study was performed using a 6-months old female black, hairless Yucatan Minipig (Sinclair ResearchCenter, Columbia, MO). The pig will was anesthetized using Telazol/Xylazine (4.4 mg/kg im + 2.2 mg/kg im). Inhalantanesthetic (Halothane or Isoflurane (1.5-3.0%) with Oxygen (3.0 L/min) was delivered by mask and filtered with an F-Air canister only if the injectable anesthetic did not provide enough somatic analgesia. The test sites were marked withmicro tattoos by applying India Ink to the corners of each test site and inserting hypodermic needles into such test sitecorners. The cold exposure was performed with a convex round copper plate attached to a heat exchanger, which waschilled by a circulating cooling agent tempered to -7°C. The exposure time ranged between 600 to 1200s. Table 3 depictsthe parameters of the cooling application and the results obtained at various sites in Pig III. The cold plate had threecentral openings of approximately 1mm in diameter through which thermocouples were placed to monitor the temperatureprofile at different depth of the tissue during cold exposure. The cold exposure device, shown in Figure 9, was firmlyheld to the test site during cold exposure. Cold exposures were performed on two different experimental days, one weekapart. On the first experimental day the thermocouples were occasionally displaced during the cold exposure leadingto a 0.5mm variability of the thermocouple depth measurement. An additional set of exposures with thermocouples wereperformed on the second experimental day at well-defined depths with minimal to no variability in the depth of thethermocouples. The location of the thermocouples on the first experimental day for test Sites 1,2,3,7,11 and12 was at2.5, 4.5 and 10 mm depth (+/- 0.5mm). Test Sites 14,15,16 and18 were treated on the second experimental day at athermocouple depth of 2, 4 and 8 mm, with minimal to no displacement. A certain variability of the thermocouple depthmay still be present due to tissue compression during the cold exposure exposure. A glycol containing solution was usedto ensure good thermal contact at the skin surface. The pig was observed for 3 � months after treatment, until sacrificedand the tissue of the test sites harvested for analysis. Table 3 depicts the parameters of the cooling application and theresults obtained at various sites in Pig III:

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Table 3

Site Temperature (coolant agent)

Exposure time Location Tempmin @ depth Tempmin @ depth Tempmin @ depth Indentation 31/2 months

Relative decrease of superficial fat layer

@ 3 �, months

1 -7 °C 5 minutes Flank 0°C@2.5mm 7°C@5mm 24°C@10mm + 66%

2 -7 °C 5 minutes Flank -2°C@2.5mm N/A 21°C@10mm +

3 Control Flank - 9%

7 -7 °C 10 minutes Abdomen -3°C@2.5mm 7°C@5mm 19°C@10mm +

9 Control Abdomen

11 -7 °C 10 minutes Buttock N/A N/A 12°C@10mm ++ 79%

12 -7°C 10 minutes Buttock -4°C@2.5mm N/A 13°C@10mm + 57%

13 -7°C 10 minutes Buttock -4°C@2mm N/A 7°C@10mm +

14 -7°C 21 minutes Buttock -4°C@2mm 3°C@4mm 12°C@8mm +

15 -7°C 11 minutes Buttock -4°C@2mm 1°C@4mm 12°C@8mm +

16 -7 °C 10 minutes Buttock - -4°C@2mm 0°C@4mm 14°C@8mm ++

18 -7°C 15 minutes Flank -3°C@2mm N/A 15°C@8mm + 66%

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[0085] The test sites were exposed to the device, set to a coolant temperature of -7°C and exposed for 600 to 1200s.The dermis hardened immediately after the cold exposure, as determined by palpation, and became viscose as it returnedto its normal temperature, approximately a minute after exposure. There was no epidermal damage or alteration evidentby close-up examination with polarized magnifier lens minutes after exposure. There was no blister formation andNikolsky-sign was negative. During the entire survival period there was no gross damage to the epidermis. No crusting,blister or pronounced pigmentary changes were observed. Some test sites exhibits a minor increase in epidermalpigmentation. This mild hyperpigmentation could be removed after few months by gentle rubbing of the epidermis.[0086] The temperature measurements of the thermocouples depended on depth, body location, and the pressurewith which cooling was applied. The temperature plots at different tissue depths during the cold exposure are shown inFigures 10 A-J for various test sites and are also summarized in Table 3. For some test sites, temperature oscillationsthat might be related to a nearby blood vessel was observed. Some temperature plots were not considered due tomovements or misplacement of the thermocouple (labeled ’error’ in table 3). The temperature within the deep dermisor superficial fat layer is within the range of -2°C to -4°C. The temperature within 4-5 mm depth is within the range ofabout 0°C to 7°C depending on variations in contact pressure and anatomical area. This location demonstrated a highvariability of the different temperature plots. The temperature within 8-10 mm depth, which corresponds to a depth withinthe subcutaneous fat layer had a temperature in the range of 7-24°C.[0087] Histology of a control (Site 9) and cold exposed site (Site 8) (-7°C, 600s) was procured 6 days post exposureand analyzed by a dermatopathologist. The following was described at the control and the cold exposed site:

The epidermis of both samples is normal and exhibits basket-woven stratum corneum with normal thickness, normalrete ridges as compared to the control. Within the cold exposed site there is a mild perivascular, lymphocytic infiltratepresent. However no frank signs of vasculitis present in both samples.

[0088] The subcutaneous fat of the control exhibit the normal morphology. The subcutaneous fat of the cold exposedsite exhibits clear signs of lobular and septal panniculitis. Most of the adipocytes are surrounded by lymphocytic infiltratewith occational lipid containing macrophages. The thickness of the subcutaneous septae is increased. Mild vascularchanges however no frank signs of vasculitis. Three and one half months after the cold exposure the pig was sacrificedand tissue at the exposure sites was harvested by full thickness excision, after 20 MHz ultrasound imaging was performedthrough selected test sites. The in-vivo ultrasound images clearly demonstrated loss of fatty tissue in the area of treatmentby skin cooling vs. the non-cold exposed surrounding tissue. An in-vivo ultrasound image 3 � months after cold exposureis shown in Figure 11.[0089] The harvested tissue was cut macroscopically through the test sites and images were taken from the macro-scopic tissue cross-sections. The macroscopic cross sections of Sites 1,3,11,12 and 18 are shown in Figure 13 A-E. Adecrease of the thickness of the subcutaneous fat layer was observed for all cold exposed sites vs. the non-cold exposedadjacent fat layer. The macroscopic cross sections matched well with the ultrasound images. Two different compartmentswithin the subcutaneous fat could be identified, a superficial fat layer and a deep fat layer. Thickness of the superficialfat layer was dramatically reduced at sites of cold treatment, while the deep fat layer was not significantly changed. Thepercentage of decrease of the superficial fat layer inside the test area vs. outside is listed for some test sites in Table3. A change of the subcutaneous fat layer was observed for cold exposed Sites 1,11,12 and 18. The average decreaseof thickness for the superficial fat layer within the evaluated test sites was 47%. For the unexposed control side, nosignificant decrease of thickness was found in either fat layer.[0090] These examples confirm that it is possible in a pig model to achieve selective tissue damage of the subcutaneousadipose tissue by external cooling within a specific range of external cooling temperature and exposure time, withoutsignificant damage to the epidermis and dermis. Removal of subcutaneous fat was also demonstrated by an obviousindentation at the treated skin surface, which matched exactly with the cooling exposure, and with the measurementsof the fat layer in relation to the cold exposure site by ultrasound and macroscopic cross sections after sacrifice. Pronoucedhistological changes, which were selective to the subcutaneous adipose tissue were observed 6 days after cold exposure.Histologically a panniculitis with a decrease in fat cell size was observed. There was evidence that the response to thecold can vary for different sites and that the more superficial fat layer is more affected by tissue loss than the deeper fatlayer. The results of Pig III however imply that there is enhanced fat removal at the superficial fat layer vs. the deeperlayer. The explanation for this is a) the superficial fat layer is exposed to colder temperatures because of the gradientand/or b) the deeper fat layer in pigs may be less susceptible to selective cold damage.[0091] Figure 9 depicts an image of the device for the cold exposure of Pig III. The cold copper plate 91 is brought incontact with the skin. The temperature profile within the skin during cold exposure is measured by thermocouples 92inserted into the tissue in different depths. The device is spring loaded 93 to provide a pressure during the cold exposure.[0092] Figures 10 depicts the temperature profile in various depths during the cold exposure of Pig III for different testSites:10A (Site 1), 10B (Site 2), 10C (Site 7), 10D (Site 11), 10E (Site 12), 10F (Site 13), 10G (Site 14), 10H (Site 15),10I (Site 16) and 10J (Site 18). The temperature in various depths is labeled with T3-E (surface), T0-B (2-2.5mm), T1-

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C (4-5mm) and T2-D (8-10mm).[0093] Figure 11 depicts an ultrasound image of test Site 11 taken 3 � months after exposure. The section below1105 is outside the cold exposed area the section below 1106 is within the cold exposed area. The dermis 1102 can beclearly distinguished from the fat layer 1103 and the muscular layer 1104. Within the fat layer 1103 two distinct layerscan be distinguished: the superficial fat layer 1103a and the deep fat layer 1103b. The ultrasound image matches wellwith the macroscopic cross section of the same tissue in Figure 13c.[0094] Figure 12 depicts histology of test Site 8 (Figure 12A and 12B) six days after cold exposure (-7°C, 600s) andtest Site 9, which is an unexposed control (Figure 12C and 12D). The micrographs show an image of low power mag-nification (1,25x) in Figures 12A and 12C and a medium power magnification (5x) in Figure 12B and 12D. The imagesshowing the epidermis 701, the dermis 702 and the subcutaneous fat 703. While the unexposed control exhibits normaltissue morphology, the cold-exposed tissue exhibits clear signs of panniculitis in the subcutaneous fat. Inflammatorycells have migrated into this area and the average fat cell size is decreased.[0095] Figures 13 A- E depict macroscopic sections through the center of different test Sites after the pig was sacrificed,3 � months after cold exposure: 13A (Site 1), 13B (Site 3), Figure 13C (Site 11), Figure 13D (Site 12) and Figure 13E(Site 18). Each Figure exhibits a scale 1300, which has 1 cm units and 1mm subunits. The epidermis 1301, the dermis1302, the superficial fat layer 1303 and the deep fat layer 1304. For the unexposed control Figure 13B no change ofthickness of different layers can be seen. Figures 13A, 13C, 13D and 13E show the cross section of cold exposed areas,which is matched to the central 4-5 cm of tissue and non-cold exposed areas surround. A decrease of thickness withinthe superficial fat layer of the cold exposed areas vs. the non-cold exposed areas can be seen in all cold exposedsamples. The change in % of thickness for each of the sample is listed in Table 3.

Claims

1. A device for selectively disrupting lipid rich cells in a non-infant human subject by cooling, while concurrently therewith,maintaining the subject’s skin at a temperature whereby non-lipid rich cells are not disrupted, the device comprising:cooling means (110), at least one feedback device (120), and a control unit (105) in communication with the at leastone feedback device (120), the control unit (105) configured to control the operation of the cooling means (110) tocool a local region of the subject’s skin to cool the lipid rich cells to a temperature between about -10°C and about25°C to selectively disrupt lipid rich cells of the region, while, concurrently therewith, maintaining the subject’s skinat a temperature whereby non-lipid rich cells are not disrupted, wherein the cooling means (110) are adapted tocool the lipid rich cells to a temperature between about -10°C and about 25°C and,wherein the device is configured to modify a shape of the local region to contour a surface ol’ the local region withinthe device.

2. The device of claim 1, wherein the cooling means (110) is adapted for the application onto the subject’s skin andincludes a conductive cooling means.

3. The device of claim 2, wherein the cooling means (110) is actively cooled and comprises a thermoelectric coolingmeans and/or a cooling agent circulating through the cooling means and/or a conductive cooling means and/or acirculating cooling agent that contacts the subject’s skin and/or an evaporative cooling means and/or cooling meansapplied to the skin by suction and/or means for applying a cooling liquid.

4. The device of any one of claims 1 to 3, wherein the cooling means (110) has a skin contacting surface and/or a flatsurface and/or a contoured surface.

5. The device of any one of claims 1 to 4, wherein the cooling means (110) is adapted to be applied to the subject’sskin with a pressure that is approximately equal to or greater than the systolic blood pressure in the subject’s dermisso as to decrease the blood flow within the dermis.

6. The device of any one of claims 1 to 4, wherein the cooling means (110) is adapted to be applied to the subject’sskin with a pressure that is approximately equal to or less than the systolic blood pressure in the subject’s dermisso as to decrease the blood flow within the dermis.

7. The device of any one of claims 1 to 4, wherein the cooling means (110) is adapted to be applied to the subject’sskin with pressure in an amount sufficient to decrease the blood flow with the dermis.

8. The device of any one of claims 1 to 7, wherein the at least one feedback device (120) includes crystal detection

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means for obtaining feedback that crystals have formed in the lipid rich cells, which feedback is used by the controlunit (105) for controlling the temperature of the cooling means (110).

9. The device of claim 8, wherein the crystal detection means is adapted to perform at least one of the followingmeasurements: optical measurement, mechanical measurement, acoustical measurement, tensile strength meas-urement, ultrasound imaging, viscosity measurement, electrical measurement or temperature measurement.

10. The device of claim 9, wherein the temperature measurement comprises the use of non-invasive or invasive devices.

11. The device of any one of claims 1 to 9, further comprising:

means for providing a mechanical motion to the lipid rich cells prior to, simultaneous with, or following applicationof the cooling means (110).

12. The device of claim 11, wherein the mechanical motion is provided by vibration and/or wherein the mechanicalmotion comprises at least one pulsation and/or wherein the mechanical motion is provided by massage.

13. The device of any one of claims 1 to 12, wherein the cooling means (110) is adapted to cool the lipid rich cells toor a temperature between about -10°C and 20°C, or a temperature between about -10°C and 15°C, or a temperaturebetween about -10°C and 10°C, or a temperature between about -10°C and 4°C, a temperature between about-4°C and 25°C, or a temperature between about -4°C and 20°C, or a temperature between about -4°C and 15°C,or a temperature between about -4°C and 10°C, or a temperature between about -4°C and 4°C, or a temperaturebetween about -2°C and 25°C, or a temperature between about -2°C and 20°C, or a temperature between about-2°C and 15°C, or a temperature between about - 2°C and 10°C, or a temperature between about -2°C and 5°C.

14. The device of any of claims 1 to 13, wherein the lipid rich cells are adipose cells within the subcutaneous tissue orcellulite.

15. The device of claim 1, further comprising:

a treatment unit (107) coupled to the cooling means (110);a suction unit (305) coupled to the treatment unit (107);a treatment interface (115) within the treatment unit (107); anda chamber (310) within the treatment unit (107);wherein the suction unit (305) is adapted to draw air from the chamber (310) and thereby pull skin into thechamber (310) and into contact with the treatment interface (115).

16. The device of claim 15, wherein the suction unit (305) is adapted to draw the region into thermal communicationwith the cooling means (110).

17. The device of claim 15, wherein the suction unit (305) is adapted to draw air to pull the subject’s skin up.

18. The device of claim 15, wherein the treatment interface (115) has a curved surface.

19. The device of claim 18, wherein the curved surface forms a dome.

20. The device of any one of claims 1 to 19, wherein the control unit (105) is further programmed to control the operationof the cooling means to maintain the cooling means (110) at an average temperature between about -15°C and35°C, or between about - 15°C and 30°C, or between about -15°C and 25°C, or between about -15°C and 20°C, orbetween about -15°C and 15°C, or between about -15°C and 10°C, or between about -15°C and 5°C, or betweenabout -10°C and 35°C, or between about -10°C and 30°C, or between about -10°C and 25°C, or between about-10°C and 20°C, or between about -10°C and 15°C, or between about -10°C and 10°C, or between about -10°Cand 5°C, or between about -5°C and 20°C, or between about -5°C and 15°C, or between about -5°C and 10°C, orbetween about -5°C and 5°C.

21. The device of any one of claims 1 to 20, wherein the control unit (105) includes hardware and/or software means.

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Patentansprüche

1. Vorrichtung zum selektiven Zerstören von lipidreichen Zellen in einem menschlichen Subjekt, das kein Kind ist,durch Kühlen, wobei gleichzeitig die Haut des Subjekts bei einer Temperatur gehalten wird, bei welcher nicht-lipidreiche Zellen nicht zerstört werden, die Vorrichtung aufweisend:

Mittel zum Kühlen (110), zumindest eine Vorrichtung zur Rückkopplung (120), eine Steuereinheit (105), die mitder zumindest einen Vorrichtung zur Rückkopplung (120) in Verbindung steht,wobei die Steuereinheit (105) zum Steuern des Betriebes der Mittel zum Kühlen (110) zur Kühlung einer lokalenRegion der Haut des Subjekts ausgeführt ist, um die lipidreichen Zellen auf eine Temperatur zwischen etwa-10°C und etwa 25°C zum selektiven Zerstören von lipidreichen Zellen der Region zu kühlen, wobei gleichzeitigdie Haut des Subjekts bei einer Temperatur gehalten wird, bei welcher nicht-lipidreiche Zellen nicht zerstörtwerden,wobei die Mittel zum Kühlen (110) ausgeführt sind, die lipidreichen Zellen auf eine Temperatur zwischen etwa-10°C und etwa 25°C zu kühlen, undwobei die Vorrichtung zur Veränderung einer Form der lokalen Region ausgeführt ist, so dass in der Vorrichtungeine Kontour einer Oberfläche der lokalen Region ist.

2. Vorrichtung nach Anspruch 1, wobei die Mittel zum Kühlen (110) angepasst sind für die Aufbringung auf die Hautdes Subjekts und ein konduktives Mittel zum Kühlen umfassen.

3. Vorrichtung nach Anspruch 2, wobei das Mittel zum Kühlen (110) aktiv gekühlt ist und ein thermoelektrisches Mittelzum Kühlen und/oder ein Kühlmittel, das durch das Mittel zum Kühlen zirkuliert und/oder ein konduktives Mittel zumKühlen und/oder ein zirkulierendes Kühlmittel, das die Haut des Subjekts kontaktiert und/oder ein verdampfendesKühlmittel und/oder ein Mittel zum Kühlen, das durch Saugen auf die Haut aufgebracht wird und/oder ein Mittel zumAufbringen einer Kühlflüssigkeit umfasst.

4. Vorrichtung nach einem der Ansprüche 1 bis 3, wobei das Mittel zum Kühlen (110) eine hautkontaktierende Ober-fläche und/oder eine flache Oberfläche und/oder eine konturierte Oberfläche aufweist.

5. Vorrichtung nach einem der Ansprüche 1 bis 4, wobei das Mittel zum Kühlen (110) angepasst ist, um auf die Hautdes Subjekts mit einem Druck aufgebracht zu werden, der ungefähr gleich oder größer ist als der systolischeBlutdruck in der Dermis des Subjekts, um so den Blutfluss innerhalb der Dermis zu verringern.

6. Vorrichtung nach einem der Ansprüche 1 bis 4, wobei das Mittel zum Kühlen (110) angepasst ist, um auf die Hautdes Subjekts mit einem Druck aufgebracht zu werden, der ungefähr gleich oder kleiner ist als der systolischeBlutdruck in der Dermis des Subjekts, um so den Blutfluss innerhalb der Dermis zu verringern.

7. Vorrichtung nach einem der Ansprüche 1 bis 4, wobei das Mittel zum Kühlen (110) angepasst ist, um auf die Hautdes Subjekts aufgebracht zu werden mit einem Druck in einer ausreichender Menge, um den Blutfluss innerhalbder Dermis zu verringern.

8. Vorrichtung nach einem der Ansprüche 1 bis 7, wobei die zumindest eine Vorrichtung zur Rückkopplung (120) einKristalldetektionsmittel zum Erhalten von Rückkopplungsinformation, dass sich Kristalle in den lipidreichen Zellengebildet haben, aufweist, wobei die Rückkopplung durch die Steuereinheit (105) zum Steuern der Temperatur derMittel zum Kühlen (110) verwendet wird.

9. Vorrichtung nach Anspruch 8, wobei das Kristalldetektionsmittel angepasst ist, um mindestens eine der folgendenMessungen auszuführen: optische Messung, mechanische Messung, akustische Messung, Zugfestigkeitsmessung,Ultraschallbildwiedergabe, Viskositätsmessung, elektrische Messung oder Temperaturmessung.

10. Vorrichtung nach Anspruch 9, wobei die Temperaturmessung die Verwendung nichtinvasiver oder invasiver Vor-richtungen umfasst.

11. Vorrichtung nach einem der Ansprüche 1 bis 9, ferner aufweisend: Mittel zum Bereitstellen einer mechanischenBewegung auf die lipidreichen Zellen vor, gleichzeitig mit oder nach der Aufbringung der Mittel zum Kühlen (110).

12. Vorrichtung nach Anspruch 11, wobei die mechanische Bewegung bereitgestellt wird durch Vibration und/oder wobei

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die mechanische Bewegung mindestens eine Pulsation umfasst und/oder wobei die mechanische Bewegung durchMassage bereitgestellt wird.

13. Vorrichtung nach einem der Ansprüche 1 bis 12, wobei das Mittel zum Kühlen (110) angepasst ist, um die lipidreichenZellen auf eine Temperatur von oder zwischen etwa - 10 und 20°C abzukühlen, oder eine Temperatur zwischenetwa -10 und 15°C, oder eine Temperatur zwischen etwa -10 und 10°C, oder eine Temperatur zwischen etwa -10und 4°C, oder eine Temperatur zwischen etwa -4 und 25°C, oder eine Temperatur zwischen etwa -4 und 20°C,oder eine Temperatur zwischen etwa -4 und 15°C, oder eine Temperatur zwischen etwa -4 und 10°C, oder eineTemperatur zwischen etwa -4 und 4°C, oder eine Temperatur zwischen etwa -2 und 25°C, oder eine Temperaturzwischen etwa -2 und 20°C, oder eine Temperatur zwischen etwa -2 und 15°C, oder eine Temperatur zwischenetwa -2 und 10°C, oder eine Temperatur zwischen etwa -2 und 5°C.

14. Vorrichtung nach einem der Ansprüche 1 bis 13, wobei die lipidreichen Zellen adipöse Zellen innerhalb des subku-tanen Gewebes oder Cellulite sind.

15. Vorrichtung nach Anspruch 1, weiterhin aufweisend: eine Vorrichtung zur Behandlung (107), die an die Mittel zumKühlen (110) gekoppelt ist; eine Vorrichtung zum Saugen (305), die an die Vorrichtung zur Behandlung (107)gehoppelt ist; eine Behandlungsschnittstelle (115) innerhalb der Vorrichtung zur Behandlung (107), und eine Kammer(310) innerhalb der Vorrichtung zur Behandlung (107); wobei die Vorrichtung zum Saugen (305) ausgeführt ist, Luftvon der Kammer (310) zu ziehen und dabei Haut in die Kammer (310) und in Kontakt mit der Behandlungsschnittstelle(115) zu ziehen.

16. Vorrichtung nach Anspruch 15, wobei die Vorrichtung zum Saugen (305) ausgeführt ist, die Region in thermischeKommunikation mit den Mitteln zum Kühlen (110) zu ziehen.

17. Vorrichtung nach Anspruch 15, wobei die Vorrichtung zum Saugen (305) ausgeführt ist, Luft anzuziehen, um dieHaut des Subjekts hoch zu ziehen.

18. Vorrichtung nach Anspruch 15, wobei die Behandlungsschnittstelle (115) eine gekrümmte Oberfläche aufweist.

19. Vorrichtung nach Anspruch 18, wobei die gekrümmte Oberfläche eine Kuppel bildet.

20. Vorrichtung nach einem der Ansprüche 1 bis 19, wobei die Steuereinheit (105) programmiert ist, den Betrieb derMittel zum Kühlen zu steuern, um eine durchschnittliche Temperatur der Mittel zum Kühlen (110) aufrecht zu haltenzwischen etwa -15 und 35°C, oder zwischen etwa -15 und 30°C, oder zwischen etwa -15 und 25°C, oder zwischenetwa - 15 und 20°C, oder zwischen etwa -15 und 15°C, oder zwischen etwa -15 und 10°C, oder zwischen etwa -15und 5°C, oder zwischen etwa -10 und 35°C, oder zwischen etwa -10 und 30°C, oder zwischen etwa -10 und 25°C,oder zwischen etwa -10 und 20°C, oder zwischen etwa -10 und 15°C, oder zwischen etwa -10 und 10°C, oderzwischen etwa -10 und 5°C, oder zwischen etwa -5 und 20°C, oder zwischen etwa -5 und 15°C, oder zwischenetwa -5 und 10°C, oder zwischen etwa -5 und 5°C.

21. Vorrichtung nach einem der Ansprüche 1 bis 20, wobei die Steuereinheit (105) Hardware und/oder Software aufweist.

Revendications

1. Dispositif destiné à perturber sélectivement les cellules riches en lipides par refroidissement chez un sujet humainqui n’est pas un nourrisson, tout en maintenant simultanément en outre la peau du sujet à une température parlaquelle les cellules qui ne sont pas riches en lipides ne sont pas perturbées, le dispositif comprenant : un moyende refroidissement (110), au moins un dispositif de retour d’informations (120), et une unité de commande (105) encommunication avec l’au moins un dispositif de retour d’informations (120), l’unité de commande (105) étant con-figurée pour commander le fonctionnement du moyen de refroidissement (110) pour refroidir une région locale dela peau du sujet pour refroidir les cellules riches en lipides à une température entre environ -10°C et environ 25°Cpour perturber sélectivement les cellules riches en lipides de la région, tout en maintenant simultanément en outrela peau du sujet à une température par laquelle les cellules qui ne sont pas riches en lipides ne sont pas perturbées,dans lequel le moyen de refroidissement (110) est adapté pour refroidir les cellules riches en lipides à une températureentre -10°C et environ 25°C, etdans lequel le dispositif est configuré pour modifier une forme de la région locale pour courber une surface de la

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région locale à l’intérieur du dispositif.

2. Dispositif selon la revendication 1, dans lequel le moyen de refroidissement (110) est adapté pour l’application surla peau du sujet et comprend un moyen de refroidissement conducteur.

3. Dispositif selon la revendication 2, dans lequel le moyen de refroidissement (110) est activement refroidi et comprendun moyen de refroidissement thermoélectrique et/ou un agent de refroidissement circulant à travers le moyen derefroidissement et/ou un moyen de refroidissement conducteur et/ou un agent de refroidissement circulant qui entreen contact avec la peau du sujet et/ou un moyen de refroidissement par évaporation et/ou un moyen de refroidis-sement appliqué sur la peau par aspiration et/ou un moyen d’application d’un liquide de refroidissement.

4. Dispositif selon l’une quelconque des revendications 1 à 3, dans lequel le moyen de refroidissement (110) a unesurface de contact avec la peau et/ou une surface plate et/ou une surface courbe.

5. Dispositif selon l’une quelconque des revendications 1 à 4, dans lequel le moyen de refroidissement (110) est adaptépour être appliqué sur la peau du sujet avec une pression qui est approximativement égale à ou supérieure à lapression sanguine systolique dans le derme du sujet de manière à diminuer la circulation sanguine dans le derme.

6. Dispositif selon l’une quelconque des revendications 1 à 4, dans lequel le moyen de refroidissement (110) est adaptépour être appliqué sur la peau du sujet avec une pression qui est approximativement égale à ou inférieure à lapression sanguine systolique dans le derme du sujet de manière à diminuer la circulation sanguine dans le derme.

7. Dispositif selon l’une quelconque des revendications 1 à 4, dans lequel le moyen de refroidissement (110) est adaptépour être appliqué sur la peau du sujet avec une pression en une quantité suffisante pour diminuer la circulationsanguine dans le derme.

8. Dispositif selon l’une quelconque des revendications 1 à 7, dans lequel l’au moins un dispositif de retour d’informations(120) comprend un moyen de détection de cristaux destiné à obtenir un retour d’informations indiquant que descristaux se sont formés dans les cellules riches en lipides, lequel retour d’informations est utilisé par l’unité decommande (105) pour commander la température du moyen de refroidissement (110).

9. Dispositif selon la revendication 8, dans lequel le moyen de détection de cristaux est adapté pour réaliser au moinsl’une des mesures suivantes : mesure optique, mesure mécanique, mesure acoustique, mesure de la résistance àla traction, imagerie par ultrasons, mesure de la viscosité, mesure électrique ou mesure de la température.

10. Dispositif selon la revendication 9, dans lequel la mesure de la température comprend l’utilisation de dispositifs noninvasifs ou invasifs.

11. Dispositif selon l’une quelconque des revendications 1 à 9, comprenant en outre :

un moyen de génération d’un mouvement mécanique pour les cellules riches en lipides avant, pendant ou aprèsl’application du moyen de refroidissement (110).

12. Dispositif selon la revendication 11, dans lequel le mouvement mécanique est généré par vibration et/ou dans lequelle mouvement mécanique comprend au moins une pulsation et/ou dans lequel le mouvement mécanique est générépar massage.

13. Dispositif selon l’une quelconque des revendications 1 à 12, dans lequel le moyen de refroidissement (110) estadapté pour refroidir les cellules riches en lipides à ou une température entre environ -10°C et 20°C, ou unetempérature entre environ -10°C et 15°C, ou une température entre environ -10°C et 10°C, ou une températureentre environ -10°C et 4°C, une température entre environ -4°C et 25°C, ou une température entre environ -4°C et20°C, ou une température entre environ - 4°C et 15°C, ou une température entre environ -4°C et 10°C, ou unetempérature entre environ -4°C et 4°C, ou une température entre environ -2°C et 25°C, ou une température entreenviron -2°C et 20°C, ou une température entre environ -2°C et 15°C, ou une température entre environ -2°C et10°C, ou une température entre environ -2°C et 5°C.

14. Dispositif selon l’une quelconque des revendications 1 à 13, dans lequel les cellules riches en lipides sont les cellulesadipeuses dans le tissu sous-cutané ou la cellulite.

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15. Dispositif selon la revendication 1, comprenant en outre :

une unité de traitement (107) couplée au moyen de refroidissement (110) ;une unité d’aspiration (305) couplée à l’unité de traitement (107) ;une interface de traitement (115) dans l’unité de traitement (107) ; etune chambre (310) dans l’unité de traitement (107) ;dans lequel l’unité d’aspiration (305) est adaptée pour extraire l’air de la chambre (310) et ainsi tirer la peaudans la chambre (310) et la mettre en contact avec l’interface de traitement (115).

16. Dispositif selon la revendication 15, dans lequel l’unité d’aspiration (305) est adaptée pour mettre la région encommunication thermique avec le moyen de refroidissement (110).

17. Dispositif selon la revendication 15, dans lequel l’unité d’aspiration (305) est adaptée pour extraire l’air afin de tirerla peau du sujet vers le haut.

18. Dispositif selon la revendication 15, dans lequel l’interface de traitement (115) a une surface courbe.

19. Dispositif selon la revendication 18, dans lequel la surface courbe forme un dôme.

20. Dispositif selon l’une quelconque des revendications 1 à 19, dans lequel l’unité de commande (105) est en outreprogrammée pour commander le fonctionnement du moyen de refroidissement pour maintenir le moyen de refroi-dissement (110) à une température moyenne entre environ -15°C et 35°C, ou entre environ -15°C et 30°C, ou entreenviron -15°C et 25°C, ou entre environ -15°C et 20°C, ou entre environ -15°C et 15°C, ou entre environ -15°C et10°C, ou entre environ -15°C et 5°C, ou entre environ -10°C et 35°C, ou entre environ -10°C et 30°C, ou entreenviron -10°C et 25°C, ou entre environ -10°C et 20°C, ou entre environ -10°C et 15°C, ou entre environ -10°C et10°C, ou entre environ -10°C et 5°C, ou entre environ -5°C et 20°C, ou entre environ -5°C et 15°C, ou entre environ- 5°C et 10°C, ou entre environ -5°C et 5°C.

21. Dispositif selon l’une quelconque des revendications 1 à 20, dans lequel l’unité de commande (105) comprend desmoyens matériels et/ou logiciels.

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the Europeanpatent document. Even though great care has been taken in compiling the references, errors or omissions cannot beexcluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 5143063 A [0006]• US 5507790 A [0006]• US 5769879 A [0006]

• WO 0044346 A [0006]• GB 2286660 A [0008]

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• Duncan et al. Arch. Derm., 1996, vol. 94, 722-724[0003]

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• Diseases of the Corium and Subcutaneous Tissue.Moschella, Samuel L. ; Hurley, Harry J. Dermatol-ogy. W.B. Saunders Company, 1985, 1169-1181[0003]

• John C Maize. Panniculitis. Cutaneous Pathology(Churchill Livingstone), 1998, 327-344 [0003]

• Disorders of Subcutaneous Fat (Cold Panniculitis).Bondei, Edward E. ; Lazarus, Gerald S. Dermatol-ogy in General Medicine. McGraw-Hill, Inc, 1993,1333-1334 [0003]

• Adipose Tissue. Renold, Albert E. ; Cahill, Jr. ;George F. Handbook of Physiology. American Phys-iology Society, 1965, 170-176 [0004]

• Burge, S. ; Dawber, R. Cryobiology, 1990, vol. 27,153-163 [0007]

• Malcom G. et al. Am. J. Clin. Nutr., 1989, vol. 50 (2),288-91 [0035]